Men and Women Reflect on Their Mistakes Differently, Study Finds

Female brains process past mistakes differently, shaped by a specific RNA. This could explain sex-based differences in depression risk and decision-making.

A type of RNA that has historically received little attention has now been found to play a key role in building resilience to depression—but only in females. In a new study led by researchers at the Icahn School of Medicine at Mount Sinai, scientists uncovered a previously unknown function of this molecule in shaping decision-making processes in the female brain.

Their findings reveal that this RNA biomarker produces sex-specific and brain-region-specific effects, influencing how individuals—based on sex—make certain types of choices. The study highlights clear differences in how males and females evaluate past mistakes, decide when to move on, and experience regret over missed opportunities.

These findings offer new insight into how mood-related decisions may engage the brains of men and women in distinct ways. Published on July 11 in Science Advances, the research used animal models to explore the biological and psychological factors that may contribute to psychiatric risk.

Women are diagnosed with depression at approximately twice the rate of men. In addition, the disorder often presents with different symptoms between sexes, such as increased tendencies toward negative rumination in women. Yet, the brain-based mechanisms that drive these differences have remained largely unexplained.

A focus on neural processing of past choices

“Our motivation for this work stemmed from a major gap in understanding why depression is more prevalent in females and how symptoms related to negative rumination take shape in the brain,” said Brian Sweis, MD, PhD, Assistant Professor of Psychiatry, and Neuroscience, at the Icahn School of Medicine and senior author of the paper. “We set out to investigate how the brain at risk for developing depression thinks about one’s prior choices and how neural circuits that process such computations could contribute to disease burden in this way.”

This research expands on a recent discovery involving a previously underappreciated group of molecules called non-coding RNA, which have been shown to play a significant role in the biological mechanisms of depression.

In a 2020 investigation that analyzed postmortem human brain samples, the same research team (Issler et al.) found that levels of a specific long intergenic non-coding RNA, known as LINC00473, were notably decreased in the prefrontal cortex of women diagnosed with major depressive disorder. This reduction was not observed in men.

Orna Issler, PhD, Assistant Professor of Neuroscience, and Anesthesiology, at the NYU Grossman School of Medicine, lead author of that 2020 study, and co-author of the present study, said, “We translated these findings into an animal laboratory model and demonstrated a causal role of prefrontal LINC00473, when experimentally increased, in promoting resilience to stress in female mice only.”

Prefrontal cortex and re-evaluation behavior

The prefrontal cortex plays a critical role in linking emotional states with decision-making processes. In this study, researchers found that altering the levels of LINC00473 in the prefrontal cortex of mice had a measurable effect on behavior—but only in females. Specifically, females with elevated LINC00473 showed greater flexibility in changing their decisions while searching for rewards, a pattern not seen in males. Using neuroeconomic approaches, the team showed that this molecular change increased females’ sensitivity to sunk costs (overvaluing past investments) and regret (awareness of missed opportunities), both of which influenced their likelihood to revise earlier choices. These behavioral traits may contribute to greater resilience under stress. Notably, this is the first evidence that non-coding RNA can directly influence cognitive functions.

“We were able to selectively alter decision-making behavior involved in re-evaluating a recently selected choice without altering the initial judgment itself,” said Romain Durand-de Cuttoli, PhD, Instructor in Neuroscience at the Icahn School of Medicine and first author of this study. “Choices that depend on reflecting on the past are neurobiologically distinguishable from those that involve planning for the future. These are fundamentally distinct types of decisions processed in separate circuits in the brain, differently in males and females, that could in turn affect emotions in unique and complex ways.”

Implications for treatment and resilience

The implications of this research are significant. The study points to a novel molecular target for new drug development as well as an anatomical target for brain stimulation therapeutics that could potentially treat depressive symptoms related to negative rumination, specifically for females. Furthermore, the study sheds light on psychological aspects of resilience vs. vulnerabilities to depression in females. This work offers new insights for establishing a mechanistic link between the neurobiology of stress responses and how affective states interact with our choices.

“This research helps us appreciate that sensitivity to regret may not always be a bad thing. There are many ‘flavors’ of regret that could come from different parts of the brain and that can manifest very differently in males and females. Ruminating on the past, while potentially unpleasant, can still be useful for learning and can contribute to how we process emotions, deal with stress, and grow from past experiences,” explained Dr. Sweis. “The challenge will be to disentangle what aspects of this are maladaptive and feed into worsening depressive symptoms and which are healthy, adaptive, and part of an intact coping strategy. It is also exciting that behavioral findings from an animal study can push us to ask new questions about human psychology in ways that could directly inform advances in psychotherapy tailored to the individual. This study is a step in the right direction toward these goals.”

Ongoing work from this group is beginning to both forward- and back-translate efforts between the lab and the clinic to examine the manyfold dimensions of decision-making that may be altered in depression.

“This work emphasizes the importance of interdisciplinary research at the intersection of multiple fields, including psychiatry, psychology, and neuroscience,” said Eric J. Nestler, MD, PhD, Interim Dean, Icahn School of Medicine at Mount Sinai; Chief Scientific Officer, Mount Sinai Health System; senior author of the Issler et al., 2020 study; and co-author of the present study. “Translational cross-species research that includes leveraging animal models is crucial for making unexpected discoveries and accelerating the development of richer diagnostics, innovative treatments, and improved outcomes for those struggling with mental illnesses.”

Reference: “Change-of-mind neuroeconomic decision-making is modulated by LINC00473 in medial prefrontal cortex in a sex-dependent manner” by Romain Durand-de Cuttoli, Orna Issler, Samantha M. B. Pedersen, Benjamin Yakubov, Nusrat Jahan, Aisha Abid, Susanna Kasparov, Kastalia Granizo, Sanjana Ahmed, Scott J. Russo, Eric J. Nestler and Brian M. Sweis, 11 July 2025, Science Advances.
DOI: 10.1126/sciadv.adr3228

This work was supported by the National Institute of Mental Health, the National Institute on Aging, the Burroughs Wellcome Fund, the Leon Levy Foundation, the New York Academy of Sciences, the Brain and Behavior Research Foundation, the Seaver Foundation, the American Society of Clinical Psychopharmacology, and the American Psychiatric Association.

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